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 �:	Pegylated Solid Lipid Nanoparticles Reconstituted from High-density Lipoprotein Components for Hepatic Targeting 

Ahmad Bani-Jabera, Huadong Cuib, Ahmed El-Saidb, Murat Yalcinb, c, Thangirala Sudhab, 
Shaker A. Mousab

a Faculty of Pharmacy, The University of Jordan, Amman, Jordan
b The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Room 238, Rensselaer, NY 12144, U.S.A.
c Department of Physiology, Veterinary Medicine Faculty, Uludag University, Gorukle, Bursa, Turkey



Correspondence: 
Shaker A. Mousa, Ph.D., MBA, FACC, FACB
 The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences
1 Discovery Drive, Room 238
 Rensselaer, NY 12144, U.S.A. 
Tel: +1 5186947397, Fax: +1 5186947567, e-mail: HYPERLINK "mailto:Shaker.mousa@acphs.edu"Shaker.mousa@acphs.edu 

Abstract 
Pegylated solid lipid nanoparticles (SLN), constituted from high-density lipoprotein components and encapsulating paclitaxel (PTX) as a model drug, were prepared to target hepatocytes and evaluated in vitro and in vivo. The SLN were prepared by a solvent-emulsification method. The composition (w/w) was 40% cholesterol esters, 18% glycerol trioleate, 8% cholesterol, and 34% pegylated distearoyl phosphatidylethanolamine. The SLN were characterized for size and drug loading. Dynamic light scattering results showed that the void and PTX-loaded SLN had mean sizes of about 154 nm and 158 nm, respectively. Cellular uptake and cytotoxicity in vitro were evaluated by confocal imaging in HepG2 (human HYPERLINK "http://en.wikipedia.org/wiki/Hepatocellular_carcinoma" \o "Hepatocellular carcinoma"hepatocellular carcinoma), MCF7 (human breast adenocarcinoma), and PANC-1 (human pancreatic cancer) cells; HepG2 cells showed the highest SLN uptake. PTX-loaded SLN or PTX solution were administered by intra-peritoneal injection into mice, and PTX concentrations in plasma, livers, hearts, lungs, and kidneys were analyzed by LC-MS/MS following liquid extraction. PTX-loaded SLN achieved longer circulation times in plasma and higher drug accumulation in liver than PTX solution.

Keywords: biodistribution; hepatocytes; high-density lipoprotein; mass spectrometry; nanoparticles; paclitaxel; pegylation; solid lipid nanoparticles

Abbreviations: DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]; HDL, high-density lipoprotein; MRM, multiple-reaction monitoring; PTX, paclitaxel; PEG, polyethylene glycol; RES, reticulo-endothelial system; SLN, solid lipid nanoparticles; t-BME, t-butyl methyl ether 
1. Introduction 
	The liver consists of hepatocytes (hepatic parenchymal cells), Kupffer cells, and endothelial cells (hepatic non-parenchymal cells) and is an important target tissue for drug therapy because many fatal diseases such as chronic hepatitis, enzyme deficiency, and hepatoma occur in hepatocytes. However, most particulate delivery systems are easily taken up within seconds or minutes after injection due to phagocytosis by the reticulo-endothelial system (RES), including Kupffer cells of the liver and macrophages of the spleen ADDIN EN.CITE  ADDIN EN.CITE.DATA  [1]. This represents a major barrier to deliver drugs to hepatocytes. 
	Paclitaxel (PTX) is a widely used chemotherapeutic agent in ovarian, breast, lung, head, and neck cancers, and Kaposi�s sarcoma ADDIN EN.CITE  ADDIN EN.CITE.DATA  [2, 3]. Additionally, some reports have shown an antitumor effect of PTX against hepatocellular carcinoma, both in vitro and in vivo  ADDIN EN.CITE  ADDIN EN.CITE.DATA  [4, 5, 6, 7]. However, due to its poor water solubility, it is formulated in poly oxy ethylated castor oil or other co-solvents, resulting in significant adverse effects ADDIN EN.CITE <EndNote><Cite><Author>Singla</Author><Year>2002</Year><RecNum>18</RecNum><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singla, A. K.</author><author>Garg, A.</author><author>Aggarwal, D.</author></authors></contributors><auth-address>University Institute of Pharmaceutical Sciences, Panjab University, 160 014, Chandigarh, India. aksingla@mailmettoday.com</auth-address><titles><title>Paclitaxel and its formulations</title><secondary-title>International Journal of Pharmaceutics</secondary-title></titles><periodical><full-title>International Journal of Pharmaceutics</full-title><abbr-1>Int. J. Pharm.</abbr-1></periodical><pages>179-92</pages><volume>235</volume><number>1-2</number><edition>2002/03/07</edition><keywords><keyword>Antineoplastic Agents, Phytogenic/administration &amp;</keyword><keyword>dosage/*chemistry/pharmacokinetics</keyword><keyword>Chemistry, Pharmaceutical/instrumentation/methods</keyword><keyword>Drug Carriers/administration &amp; dosage/chemistry/pharmacokinetics</keyword><keyword>Drug Delivery Systems/instrumentation/methods</keyword><keyword>Paclitaxel/administration &amp; dosage/*chemistry/pharmacokinetics</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar 20</date></pub-dates></dates><isbn>0378-5173 (Print)&#xD;0378-5173 (Linking)</isbn><accession-num>11879753</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11879753</url></related-urls></urls><electronic-resource-num>S0378517301009863 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote> [8]. To overcome this toxicity, Abraxane�, a nanoparticle comprising PTX and serum albumin, was developed. Other drug delivery systems for PTX formulations have been tried including liposomes, polymeric micro- and nanoparticles, polymeric micelles, lipid emulsions, and micro-emulsions ADDIN EN.CITE  ADDIN EN.CITE.DATA  [9]. 
 	Lipid-based nanoparticle systems have been looked at for anticancer agents instead of synthetic polymers ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2011</Year><RecNum>20</RecNum><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, R.</author><author>Eun, J. S.</author><author>Lee, M. K.</author></authors></contributors><auth-address>College of Pharmacy, Woosuk University, Jeonbuk, Korea.</auth-address><titles><title>Pharmacokinetics and biodistribution of paclitaxel loaded in pegylated solid lipid nanoparticles after intravenous administration</title><secondary-title>Archives of Pharmacal Research</secondary-title></titles><periodical><full-title>Archives of Pharmacal Research</full-title><abbr-1>Arch. Pharmacal Res.</abbr-1></periodical><pages>331-7</pages><volume>34</volume><number>2</number><edition>2011/03/08</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents, Phytogenic/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Drug Carriers</keyword><keyword>Injections, Intravenous</keyword><keyword>Lipids</keyword><keyword>Male</keyword><keyword>Nanoparticles/administration &amp; dosage/analysis</keyword><keyword>Paclitaxel/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Particle Size</keyword><keyword>Rats</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0253-6269 (Print)&#xD;0253-6269 (Linking)</isbn><accession-num>21380818</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21380818</url></related-urls></urls><electronic-resource-num>10.1007/s12272-011-0220-2</electronic-resource-num><language>eng</language></record></Cite></EndNote> [10]. Solid lipid nanoparticles (SLN) have been looked at because of their biocompatibility and effective sustained release ADDIN EN.CITE <EndNote><Cite><Author>Souto</Author><Year>2009</Year><RecNum>21</RecNum><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Souto, E. B.</author><author>Doktorovova, S.</author></authors></contributors><auth-address>Department of Pharmaceutical Technology, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal.</auth-address><titles><title>Chapter 6 - Solid lipid nanoparticle formulations pharmacokinetic and biopharmaceutical aspects in drug delivery</title><secondary-title>Methods in Enzymology</secondary-title></titles><periodical><full-title>Methods in Enzymology</full-title><abbr-1>Methods Enzymol.</abbr-1></periodical><pages>105-29</pages><volume>464</volume><edition>2009/11/12</edition><keywords><keyword>*Chemistry, Pharmaceutical</keyword><keyword>Drug Administration Routes</keyword><keyword>Drug Delivery Systems</keyword><keyword>Lipids/*chemistry/pharmacokinetics</keyword><keyword>Nanoparticles/*chemistry</keyword></keywords><dates><year>2009</year></dates><isbn>1557-7988 (Electronic)&#xD;0076-6879 (Linking)</isbn><accession-num>19903552</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=19903552</url></related-urls></urls><electronic-resource-num>S0076-6879(09)64006-4 [pii]&#xD;10.1016/S0076-6879(09)64006-4</electronic-resource-num><language>eng</language></record></Cite></EndNote> [11]. Reports suggested that SLN are cleared from systemic circulation via the RES ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2011</Year><RecNum>20</RecNum><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, R.</author><author>Eun, J. S.</author><author>Lee, M. K.</author></authors></contributors><auth-address>College of Pharmacy, Woosuk University, Jeonbuk, Korea.</auth-address><titles><title>Pharmacokinetics and biodistribution of paclitaxel loaded in pegylated solid lipid nanoparticles after intravenous administration</title><secondary-title>Archives of Pharmacal Research</secondary-title></titles><periodical><full-title>Archives of Pharmacal Research</full-title><abbr-1>Arch. Pharmacal Res.</abbr-1></periodical><pages>331-7</pages><volume>34</volume><number>2</number><edition>2011/03/08</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents, Phytogenic/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Drug Carriers</keyword><keyword>Injections, Intravenous</keyword><keyword>Lipids</keyword><keyword>Male</keyword><keyword>Nanoparticles/administration &amp; dosage/analysis</keyword><keyword>Paclitaxel/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Particle Size</keyword><keyword>Rats</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0253-6269 (Print)&#xD;0253-6269 (Linking)</isbn><accession-num>21380818</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21380818</url></related-urls></urls><electronic-resource-num>10.1007/s12272-011-0220-2</electronic-resource-num><language>eng</language></record></Cite></EndNote> [10]. Small particle elimination from the circulation is generally enhanced by opsonization, which leads to phagocytosis ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2006</Year><RecNum>22</RecNum><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Y.</author><author>Wu, W.</author></authors></contributors><auth-address>School of Pharmacy, Fudan University, Shanghai, China.</auth-address><titles><title>In situ evading of phagocytic uptake of stealth solid lipid nanoparticles by mouse peritoneal macrophages</title><secondary-title>Drug Delivery</secondary-title></titles><periodical><full-title>Drug Delivery</full-title><abbr-1>Drug Deliv.</abbr-1></periodical><pages>189-92</pages><volume>13</volume><number>3</number><edition>2006/03/25</edition><keywords><keyword>Animals</keyword><keyword>Drug Carriers/chemical synthesis/*chemistry/*pharmacology</keyword><keyword>Flow Cytometry</keyword><keyword>Lipids/*chemistry</keyword><keyword>Macrophages, Peritoneal/drug effects/*physiology</keyword><keyword>Mice</keyword><keyword>Nanostructures/*chemistry</keyword><keyword>Particle Size</keyword><keyword>Phagocytosis/drug effects/*physiology</keyword><keyword>Polyethylene Glycols/chemistry</keyword><keyword>Polyvinyl Alcohol/chemistry</keyword><keyword>Rhodamines/chemistry</keyword><keyword>Stearic Acids/chemistry</keyword></keywords><dates><year>2006</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>1071-7544 (Print)&#xD;1071-7544 (Linking)</isbn><accession-num>16556570</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16556570</url></related-urls></urls><electronic-resource-num>H73862047153238H [pii]&#xD;10.1080/10717540500315930</electronic-resource-num><language>eng</language></record></Cite></EndNote> [12]. Consequently, SLN would accumulate in the liver (in Kupffer cells but not in the hepatocytes) and spleen by passive targeting after parenteral administration ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2009</Year><RecNum>25</RecNum><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, M. D.</author><author>Muller, R. H.</author></authors></contributors><auth-address>Department of Pharmaceutical Technology, Biopharmaceutics and NutriCosmetics, Freie Universitate Berlin, Berlin, Germany. medhajosh@yahoo.com</auth-address><titles><title>Lipid nanoparticles for parenteral delivery of actives</title><secondary-title>European Journal of Pharmaceutics and Biopharmaceutics</secondary-title></titles><periodical><full-title>European Journal of Pharmaceutics and Biopharmaceutics</full-title><abbr-1>Eur. J. Pharm. Biopharm.</abbr-1><abbr-2>Eur J Pharm Biopharm</abbr-2><abbr-3>European Journal of Pharmaceutics &amp; Biopharmaceutics</abbr-3></periodical><pages>161-72</pages><volume>71</volume><number>2</number><edition>2008/10/01</edition><keywords><keyword>Adsorption</keyword><keyword>Animals</keyword><keyword>Drug Carriers/*chemistry</keyword><keyword>Drug Delivery Systems</keyword><keyword>Humans</keyword><keyword>Lipids/*chemistry</keyword><keyword>*Nanoparticles</keyword><keyword>Pharmaceutical Preparations/administration &amp; dosage/adverse effects</keyword><keyword>Proteins/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1873-3441 (Electronic)&#xD;0939-6411 (Linking)</isbn><accession-num>18824097</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18824097</url></related-urls></urls><electronic-resource-num>S0939-6411(08)00339-1 [pii]&#xD;10.1016/j.ejpb.2008.09.003</electronic-resource-num><language>eng</language></record></Cite></EndNote> [13]. Pegylation with polyethylene glycol (PEG) of nanoparticles increases the blood half-life after injection by reducing opsonization and reducing the uptake by macrophages into the RES ADDIN EN.CITE  ADDIN EN.CITE.DATA  [14, 15]. Pegylation also decreases renal clearance, especially when using PEG chains greater than 20�kDa ADDIN EN.CITE  ADDIN EN.CITE.DATA  [16, 17].
	Lipoproteins and in particular high-density lipoprotein (HDL) play an important role in lipid transport and in reverse cholesterol transport ADDIN EN.CITE  ADDIN EN.CITE.DATA  [18, 19]. Endogenous HDL particles are biodegradable, do not elicit immunologic responses, and exhibit longer residence time in the circulation than other lipoproteins ADDIN EN.CITE  ADDIN EN.CITE.DATA  [20]. However, development of HDL as a clinically viable nano carrier may be difficult because lipoproteins are isolated from fresh donor plasma, which might result in batch-to-batch variation and scale-up challenges ADDIN EN.CITE  ADDIN EN.CITE.DATA  [21]. Therefore, an alternative HDL-like system that is prepared from lipid without apolipoproteins represents a promising strategy ADDIN EN.CITE  ADDIN EN.CITE.DATA  [19, 22, 23]. Hence, HDL-like SLN may also be constituted from the lipid portion of native HDL without apolipoproteins, which is more favorable to scale-up ADDIN EN.CITE  ADDIN EN.CITE.DATA  [24].
	In the present study, surface-modified SLN constituted from apolipoprotein-free high-density lipoprotein components were prepared for PTX delivery to the liver. Surface modification was achieved using pegylated phospholipid in order to have prolonged blood circulation time and reduced mononuclear phagocyte system uptake. The uptake of the nanoparticles by HepG2, MCF7, and PANC-1 cells was evaluated in vitro by confocal imaging. PTX encapsulated in pegylated SLN was administered by intra-peritoneal injection into mice, and pharmacokinetics and organ distribution of PTX were compared with those when PTX was administered as a solution formulation.

2. Materials and methods

2.1 Materials 

	PTX and docetaxel of more than 97% purity were purchased from Sigma Aldrich (St. Louis, MO). Cholesterol was purchased from ICN Biochemicals, Inc. (Cleveland, OH). Cholesteryl oleate was supplied by Alfa Aescar/Johnson Matthey Co., Ltd (Ward Hill, MA). Glycerol trioleate was a product of Tokyo Chemical Industry Co., Ltd. (Japan). DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt), was from Avanti Polar Lipids Inc. (Alabaster, AL). HPLC grade methanol, acetonitrile, and t-butyl methyl ether (t-BME) were from Fisher Scientific (Pittsburg, PA). Formic acid and Fluorescein isothiocyanate (FITC) were obtained from Fluka (Saint Louis, MO).

2.2 Preparation of SLN

	The composition of SLN (w/w) was 40% cholesterol esters, 18% glycerol trioleate, 8% cholesterol, and 34% DSPE-PEG. The SLN were prepared using the emulsification/solvent evaporation method ADDIN EN.CITE  ADDIN EN.CITE.DATA  [24]. Chloroform solutions of PTX (100 �L, 5 mg/mL), cholesteryl oleate (97 �L, 30 mg/mL), glycerol trioleate (87 �L, 15 mg/mL), cholesterol (60 �L, 10 mg/mL), and DSPE-PEG (250 �L, 10 mg/mL) were mixed. Double-distilled water (5 mL) was added to the mixture followed by homogenization for 1 min to obtain an emulsion. Chloroform was evaporated from the emulsion at 50�C with stirring for 2 h. The formulation was sonicated (Bronson Sonifier W-250, Heineman, Schw�bisch, Germany) at power level 10 for 90 s. The dispersion was dialyzed against deionized water for 3 h. Void SLN with no drug incorporated were also prepared according to this procedure.

2.3 Measurement of SLN particle size 

	Size distributions of void SLN and SLN encapsulating PTX were determined by using a Malvern Zetasizer (Malvern Instruments, Westborough, MA). The nanoparticle dispersion (1 mL) was placed in a 4-sided clear plastic cuvette and analyzed at 25�C.

2.4 Evaluation of PTX loading

	An aliquot (50 �L) of PTX-loaded SLN dispersion was dissolved in 950 �L of acetonitrile. Further dilution (1:10) was performed using 70% acetonitrile. The amount of PTX was determined by an LC-MS/MS method (see below). Loading efficiency (%) was calculated using the following formula:
Loading efficiency (%) = (amount of PTX in SLN " amount of PTX used in the formulation) ( 100.

2.5 Cells and cell culture

	HepG2, MCF7, and PANC-1 cells were purchased from American Type Culture Collection  (Manassas, VA) and cultured using a complete growth medium consisting of Dulbecco's modified Eagle medium (DMEM) with 10% fetal bovine serum (FBS) obtained from Life Technologies, Gibco (Grand Island, NY). Cells were cultured in 5% CO2/air atmosphere at 37�C and then treated with 0.25% (w/v) trypsin/EDTA to affect cell release from the culture vessel. After washing the cells with culture medium, cells were suspended in DMEM. 

2.6 Confocal microscopy

	FITC-labeled nanoparticles were prepared by reacting the isothiocyanate group of FITC and the primary amino group of DSPE-PEG in the nanoparticles. To 2 mL of SLN, 10 �L of FITC in ethanol (2.5 mg/mL) were added, followed by stirring for 1 h. Free FITC was removed by dialysis against deionized water. Cells (HepG2, MCF7, and PANC-1) were grown in DMEM supplemented with10%FBS. Penicillin and streptomycin (1%) were present in the culture media. The cells were trypsinized and centrifuged, and the cell pellet was re-suspended in the corresponding media. The cells in 2�mL culture medium were put into a 6-well plate with a coverslip in each well. The cells were allowed to grow to 70 80% confluence. The cells were treated with 100 �L of FITC-labeled nanoparticles and incubated (37�C, 5% CO2/95% air) for 2 h. After incubation, the plate was washed with PBS, fixed in 4% paraformaldehyde (Sigma Aldrich) at room temperature for 10 min, and then washed with PBS. The coverslips were mounted on microscope glass slides using fluorescent mounting medium and sealed. Confocal images were obtained with a Leica TCS SP5 confocal microscope (Leica Microsystems, Wetzlar, Germany), using a 40X oil immersion objective lens and an excitation wavelength of 488 nm. 

2.7 Animal studies

	The animal study was performed in the animal research facility of the Veteran Affairs Medical Center, Albany, New York, and the experimental protocol was approved by the Veteran Affairs Institutional Animal Care and Use Committee. Male C57BL/6 mice, ranging from 4-5 weeks old and weighing 20-22 g, were obtained from Harlan Laboratories (Indianapolis, IN). Mice were housed as 4 animals per cage under climate-controlled conditions of temperature (20�24�C), humidity (60�70%), and alternating 12 h light/dark cycles. Mice were fed commercial chow diet (Prolab RMH 3000, PMI, St. Louis, MO) and water was provided ad libitum. On the day of experiment, mice were randomly assigned to one of 4 groups (3 mice per group). Two groups were subjected to a single intra-peritoneal injection of SLN nanoparticles encapsulating PTX (PTX-SLN) or PTX solution in 20% ethanol/PBS at equivalent PTX dose of 0.55 mg/kg. The remaining groups served as controls for the administration of vehicles of the formulations. Blood samples (75 �L) were collected at time 0, before drug administration, and at 30 min, 1 h, 2 h, 3 h, and 6 h after drug administration from the retro-orbital venous plexus via heparinized capillary tubes containing 2 USP units of ammonium heparin (Carolina, Burlington, NC) per tube. After the last blood collection (6 h), mice were terminated and livers, hearts, lungs, and kidneys were collected. Blood samples and organs were kept at -80�C until LC-MS/MS analysis. 

2.8 LC-MS/MS sample preparation

	Exact amounts of PTX and docetaxel (as internal standard) were weighed and dissolved in 80% acetonitrile to obtain PTX and docetaxel stock solutions, at concentrations of 2.5 mg/mL and 2 mg/mL, respectively. The stock solutions were stored at -80�C. Working solutions of PTX (20 �g/mL) and docetaxel (0.5 �g/mL), were freshly prepared daily from the stock solutions. 
	Calibration curve samples were prepared by spiking blanks of plasma and liver homogenate obtained from an untreated mouse with different volumes of PTX working solution to obtain sample drug concentrations ranging from 7.8 to 1000 ng/mL. Plasma samples were prepared from collected blood samples (50 �L) from mice after treatment with PTX-SLN or PTX solution diluted with saline and then centrifuged. Frozen organ samples were thawed and physiological saline (1 mL) was added, and each organ sample was homogenized. The homogenate was centrifuged to obtain clear supernatant. To 70 �L plasma or supernatant of organ homogenate in a 2.0 mL plastic tube, 20 �L of docetaxel working solution was added as an internal standard, and the solution was mixed. Extraction was performed with 600 �L t-BME by vortex-mixing for 10 min. After centrifugation, the supernatant was transferred into another tube and dried under N2 blowing. The residue was re-dissolved in 180 �L of 70% acetonitrile containing 0.1% formic acid, and 20 �L was injected into the LC-MS/MS for analysis.

2.9 LC-MS/MS analysis

	LC-MS/MS analysis was performed using an API 4000 triple-quadrupole tandem mass spectrometer (Applied Biosystems MSD Sciex, Grand Island, NY) equipped with two Shimadzu HPLC pumps (LC-20AD), an auto-sampler (SIL-20AC), and a column oven (CTO-20AC). Chromatographic analysis was done using a SunfireTM C18 analytical column, 3.5 �m particle size, 3.0 ( 20 mm (Waters, Milford, MA). The mobile phase consisted of 70% acetonitrile and 30% water containing 0.1% formic acid, delivered at a flow rate of 0.35 mL/min. Under these conditions, PTX and docetaxel were simultaneously eluted at 0.5 min. The mass spectrometer was operated in positive electrospray mode with the ion spray voltage set to 3.5 kV and the temperature set to 600�C. The collision gas, curtain gas, ion source gas1 and gas2 were set at 4, 20, 30 and 20 L/min, respectively. Analytes were detected by using multiple-reaction monitoring (MRM). Mass transitions were monitored at 876.4/308.1 (m/z) for PTX and 830.5/549.3 (m/z) for docetaxel. All data were acquired and processed with Analyst 1.4.2 software (Applied Biosystems MSD Sciex).

3. Results and Discussion

3.1 Characterization of SLN

	Void SLN and PTX-SLN were subjected to particle size analysis to confirm that they were in the sub-micron range. According to the criteria of the Malvern Zeta Sizer analysis program, the nanoparticles followed a Gaussian distribution, which means they were mono-disperse in their size distribution. As a result of volume-weighted Gaussian analysis, PTX-SLN had a 158 nm mean diameter (Fig. 1A), corresponding to 154 nm for void SLN (Fig. 1B). Poly dispersity index (PDI) values were 0.221 and 0.240 for void SLN and PTX-SLN, respectively. It was found that the percentage drug loading in PTX-SLN was 25.91 � 0.48%.

3.2 Cellular uptake of SLN

	Confocal images for the uptake of FITC-labeled SLN by MCF7, HepG2, and PANC-1 cells are shown in Fig. 2. The strongest fluorescent intensity was shown by HepG2 cells followed by MCF7. PANC-1 cells showed the least intensity. In addition, the uptake of nanoparticles by HepG2 cells showed more homogenous distribution over the cytoplasm and nucleus than that by MCF7 and PANC-1 cells. Consequently, the images suggest variable nanoparticle uptake among the different studied cell lines. The highest uptake by HepG2 cells could be attributed to the lipoidal core of the nanoparticles with components that mimic the core of high-density lipoproteins. 

3.3 Animal studies

	Fig. 3A shows the calibration curve of PTX spiked into mouse plasma and detected with LC-MS/MS, and representative LC-MS/MS MRM chromatograms of PTX and docetaxel (as internal standard) spiked into mouse plasma and liver homogenate are shown in Fig. 3B. The mice plasma concentrations of SLN-PTX and PTX are listed in Table 1. PTX was rapidly absorbed and reached a maximum concentration at 1 h, and then it was rapidly eliminated to become undetectable after 2 h. PTX-SLN declined slowly and remained detectable for 3 h after administration. In a previous study, pharmacokinetics of PTX were done for a pegylated PTX-SLN formulation similar to our formulation, however, the lipid component was trimyristin stabilized by egg phosphatidylcholine and DSPE-PEG. That formulation showed more drug clearance from plasma than PTX solution when administered as a single intravenous dose to rats, which was not expected for a pegylated SLN ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2011</Year><RecNum>20</RecNum><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="wwwssr2r5epa2fetewqvxztuxds5fpa9wr5t">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, R.</author><author>Eun, J. S.</author><author>Lee, M. K.</author></authors></contributors><auth-address>College of Pharmacy, Woosuk University, Jeonbuk, Korea.</auth-address><titles><title>Pharmacokinetics and biodistribution of paclitaxel loaded in pegylated solid lipid nanoparticles after intravenous administration</title><secondary-title>Archives of Pharmacal Research</secondary-title></titles><periodical><full-title>Archives of Pharmacal Research</full-title><abbr-1>Arch. Pharmacal Res.</abbr-1></periodical><pages>331-7</pages><volume>34</volume><number>2</number><edition>2011/03/08</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents, Phytogenic/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Drug Carriers</keyword><keyword>Injections, Intravenous</keyword><keyword>Lipids</keyword><keyword>Male</keyword><keyword>Nanoparticles/administration &amp; dosage/analysis</keyword><keyword>Paclitaxel/*administration &amp; dosage/*pharmacokinetics</keyword><keyword>Particle Size</keyword><keyword>Rats</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0253-6269 (Print)&#xD;0253-6269 (Linking)</isbn><accession-num>21380818</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21380818</url></related-urls></urls><electronic-resource-num>10.1007/s12272-011-0220-2</electronic-resource-num><language>eng</language></record></Cite></EndNote> [10]. Our pegylated PTX-SLN formulation, which had higher plasma levels than PTX solution and had the same core components as HDL nanoparticles, likely avoided uptake by the reticulo-endothelial system to some extent. Accordingly, it can be emphasized that biomimetic core components played a role in this suggested avoidance. The contribution of pegylation to this avoidance could not be studied because it was not possible to prepare the submicron-sized nanoparticles containing PTX without using pegylated phospholipid as stabilizer. However, the contribution of pegylation to this avoidance cannot be excluded. Despite this suggested avoidance, the accumulation of PTX in liver after 6 h of PTX-SLN administration was 8.5-, 8.9-, and 17-fold higher than in lung, kidney, and heart, respectively (Table 2). These results suggest that SLN were preferably taken up by the hepatocytes of the liver compared to the cells of other studied organs. The lipid core of SLN mimicking that of HDL nanoparticles likely played a role in this selective uptake. In addition, the plasma apolipoproteins could be adsorbed on the surface of the SLN, thereby mimicking natural apolipoprotein-containing HDL nanoparticles. The higher relative accumulation in the liver for SLN compared to plain PTX suggested that PTX was predominantly not released in the plasma from the PTX-SLN and remained incorporated in the PTX-SLN.

Acknowledgment

This work was carried out during sabbatical leave granted to Ahmad Bani-Jaber from the University of Jordan during the academic year 2010�2011. Special thanks to Kelly A. Keating of the Pharmaceutical Research Institute at the Albany College of Pharmacy and Health Sciences for outstanding editing of this manuscript

Conflict of Interest and Financial Disclosure

The authors declare they have no conflicts of interest. This research was supported by the Pharmaceutical Research Institute.
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Figure Legends

Figure 1: The size distribution measured by dynamic light scattering of (A) PTX-SLN (paclitaxel encapsulated in solid lipid nanoparticles), size about 154 nm, and (B) void SLN, size about 158 nm. Abbreviation: d nm, diameter in nm.

Figure 2: Representative confocal images illustrating the uptake of FITC-labeled SLN (solid lipid nanoparticles) by cell lines (A) MCF7, (B) HepG2, and (C) PANC-1.

Figure 3: (A) The calibration curve of paclitaxel spiked into mouse plasma, extracted with t-BME, and detected with LC-MS/MS. (B)-(D) $%&8;<Q_`ghrs�������������������ʹ����ʤ���o��_����K�'h�/�h�/�0JCJH*OJQJ^JaJhq�0JCJOJQJ^JaJ h�X�h�{�CJOJQJ^JaJ!h�/�0JCJH*OJQJ^JaJ$h�X�h�{�0JCJOJQJ^JaJh�{� h�&95�CJ OJQJ\�^JaJ  h�{�5�CJ OJQJ\�^JaJ &h*a�h�{�5�CJ OJQJ\�^JaJ  h�L5�CJ OJQJ\�^JaJ  h.=:5�CJ OJQJ\�^JaJ rs���	�	



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